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Regular Articles |
From the Division of Allergy,*
La Jolla Institute for
Allergy and Immunology, San Diego, California; the Department of
Molecular and Experimental Medicine,
the
Scripps Research Institute, La Jolla, California; and the R.W. Johnson
Pharmaceutical Research Institute,
La
Jolla, California
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Abstract |
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B response. In addition, dramatically different
cell-spreading phenotypes were observed in cultured macrophages from
the two genotypes. Whereas macrophages from gal3+/+ mice
exhibited well spread out morphology, those from
gal3-/- mice were often spindle-shaped. Finally,
we found that peritoneal macrophages from gal3-/- mice
were more prone to undergo apoptosis than those from
gal3+/+ mice when treated with apoptotic stimuli,
suggesting that expression of galectin-3 in inflammatory cells may lead
to longer cell survival, thus prolonging inflammation. These
results strongly support galectin-3 as a positive regulator of
inflammatory responses in the peritoneal cavity.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A number of biological activities of galectin-3 have been demonstrated in vitro. This lectin has been shown to activate various cells, including mast cells,15,16 neutrophils,17 monocytes/macrophages,12 and lymphocytes.14,18 The effects of this lectin in cell adhesion have also been demonstrated.19-21 These extracellular functions suggest a possible role for this protein in modulation of immune reactions and inflammatory responses. In addition, evidence for various intracellular activities of galectin-3 are also available. It has been identified as a component of hnRNP,22 as well as a factor in pre-mRNA splicing,23 and shown to have anti-apoptotic activity, possibly through a mechanism involving its interactions with Bcl-2 family members, with which this lectin shares sequence similarity.24,25
Galectin-3 has been found to be overexpressed in certain pathological conditions, including human atherosclerotic lesions.26 The association of this lectin with neoplastic transformation has also been extensively documented. It is overexpressed in some types of cancer for which the normal parental cells do not express the protein; the examples include specific types of lymphoma,14,27 thyroid carcinoma,28,29 and hepatocellular carcinoma.30 However, down-regulation of this lectin has been observed in other kinds of neoplasms, including colon,31,32 breast,33 ovarian,34 and uterine carcinoma,35 although it has also been observed that galectin-3 expression correlates positively with the progression of colon carcinoma.36,37 Studies of cells transfected with galectin-3 cDNA have indeed provided evidence for its role in tumor transformation and metastasis.38
Therefore, functions of galectin-3 appear to be multifaceted, extending to both intracellular and extracellular compartments. Because of its wide tissue distribution and pleiotropic effects in many systems, galectin-3 is likely to be involved in a variety of physiological and pathological processes. In an attempt to elucidate more definitively the biological functions of galectin-3, we have generated a mouse model in which this gene is inactivated through homologous recombination. We initially focused on the study of inflammatory responses in these mice and have found that the galectin-3 deficiency results in significantly altered inflammation elicited in the peritoneal cavity by thioglycollate broth.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A vector used for homologous recombination was constructed from
the cloned galectin-3 genomic DNA.39
As shown in Figure 1, a
segment from exon 4 to exon 5 within
the mouse galectin-3 gene was inserted into pMC1Neo (Stratagene, La
Jolla, CA) upstream of the thymidine kinase promoter-Neo
cassette. Another segment from exon 5 to exon 6 followed
downstream from the Neo cassette. Thus, exon 5 is interrupted by the
Neo gene in this vector construct. Murine stem cells, D3, were
electroporated with this vector, using procedures previously
described.40
G418 resistant cells were screened for
homologous recombination by polymerase chain reaction (PCR) and
Southern blotting, using procedures described below. Screening of 894
clones resulted in two with successful homologous recombination.
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Polymerase Chain Reaction and Southern Blot Analysis
Polymerase chain reactions were performed under standard
conditions using Taq DNA polymerase (Promega, Madison, WI)
on a Perkin-Elmer 9600 or Ericomp EZ cycler. Southern blotting analyses
were performed by capillary transfer of DNA to charged nylon membranes
(BioRad, Richmond, CA or Amersham, Arlington Heights, IL). Membranes
were probed with an intron 3 fragment corresponding to probe 1, or
probe 4 corresponding to the Neo cassette, to determine homologous
recombination, as shown in Figure 1B
, radiolabeled by random priming
with [32P]-dATP.
Immunoblot Analysis
Tissues were extracted with 20 mmol/L Tris-HCl, pH 7.5 containing 10 mmol/L EDTA, 0.15 mol/L NaCl, 1% Triton X-100 (v/v) and protease inhibitors 0.24 u/ml Aprotinin, 1 µg/ml pepstatin, 1 µg/ml leupeptin, 1 mmol/L phenylmethylsulfonyl fluoride, and 100 µg protein from each extract was then adsorbed with lactosyl-Sepharose 4B.41 The bound proteins were eluted, separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and analyzed by immunoblotting using specific rabbit antibodies as described.12
Induction of Peritoneal Inflammation
Mice were injected with 1 ml of autoclaved Brewer’s thioglycollate broth as described.42 At various intervals, peritoneal cells were harvested by lavage with minimum essential medium containing Earle’s salts (MEM). Cells were washed once with culture medium before subsequent manipulations. For quantitation of leukocyte subpopulations, the cells in the lavage fluid were allowed to attach to glass slides by cytospin, treated with soluble Wright’s stain (Leukostat, Fisher Scientific, Pittsburgh, PA) and identified as macrophages, eosinophils, neutrophils, and lymphocytes by standard morphology. Cell counts were obtained in triplicate for each sample from 100–200 cells using a 100x oil immersion objective.
Electrophoretic Mobility Shift Assay (EMSA)
Nuclear extracts were prepared by a previously described
method43
with slight modifications44
and EMSA
was performed as described.45
Briefly, the nuclear
extracts (2.5 µg protein) in 12 µl of binding buffer (5 mmol/L
HEPES, pH 7.8, 5 mmol/L MgCl2, 50 mmol/L KCl, 0.5
mmol/L dithiothreitol, 0.4 mg/ml poly(dI-dC) (Pharmacia, Piscataway,
NJ), 0.1 mg/ml sonicated double-stranded salmon sperm DNA, and
10% glycerol) were incubated for 10 minutes at room temperature.
Subsequently, approximately 20 to 50 fmoles of
32P-labeled NF-B-specific oligonucleotide
probe (30,000–50,000 cpm) were added and the reaction mixture was
incubated for 10 minutes at room temperature. The samples were analyzed
on 6% polyacrylamide gels in 50 mmol/L Tris-borate buffer containing 1
mmol/L EDTA or 50 mmol/L Tris/380 mmol/L glycine/2 mmol/L EDTA, at 12
V/cm for 2 to 2.5 hours. Radioactivities were detected by exposure
to X-ray film or phosphorimager plates.
Culture and Measurement of Adhesion Areas of Peritoneal Macrophages
Peritoneal macrophages were enriched by adherence onto tissue culture-treated plates in Dulbecco’s modified Eagle’s medium (DMEM), supplemented with 2 mmol/L glutamine and 10% (v/v) fetal bovine serum, at 37°C in an atmosphere of 7.5% CO2. After two hours of incubation, wells were gently pipetted to remove nonadherent cells. More than 90% of the adherent cells were macrophages as evaluated morphologically after processing with Wright’s stain. Initially nonadherent cells were obtained after two serial adherence procedures in tissue culture flasks. Culturing of these cells resulted in additional adherent macrophages. The morphology of adherent macrophages cultured for various periods were imaged from three fields of each well using a Hamamatsu XC-77 CCD camera attached to a Nikon microscope with an inverted stage. Image-1 from Universal Imaging Corporation was used to acquire and enhance image contrast, and NIH Image software was used to measure cell attachment areas from three random fields.
Induction of Apoptosis of Peritoneal Macrophages in Vitro
Inflammatory peritoneal macrophages were obtained from mice
treated with 1 ml thioglycollate broth for 3 days by lavage, and
cultured in RPMI/10% fetal bovine serum (RP10F) for 1 hour. Adherent
cells were cultured in the presence of 10 µg/ml lipopolysaccharide
(LPS, Escherichia coli 0111:B4 List Biologicals,
Campbell, CA) and 10 U/ml interferon-
(IFN-,
Boehringer/Roche, Indianapolis, IN), and cell viability was measured by
the MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium
bromide) assay46
at regular intervals.
Alternatively, inflammatory macrophages obtained from peritoneal
cavities of mice 4 days after 2 ml thioglycollate treatment, were
cultured for 30 minutes in RPMI 1640. The adherent cells were exposed
to 0 to 60 U/ml IFN- in RP10F for 6 hours washed with RP10F, and
then 1 µg/ml LPS in RP10F for 24 hours.47
The cells were
washed with phosphate-buffered saline, pH 7.2, fixed in 5%
formaldehyde/phosphate-buffered saline, and stained with 0.05% crystal
violet in 20% EtOH. Absorbance at 550 nm in methanol due to the
stained adherent cells was measured after the wells were
extensively washed with deionized water.
Detection of Apoptotic Macrophages by Annexin-V Binding
Inflammatory peritoneal exudate cells (5 x
106/ml) were cultured in Teflon beakers in the
presence of IFN- for 6 hours, washed, and then incubated with
1 µg/ml LPS as described above. At various time points, cells were
removed and stained with annexin-V-fluorescein isothiocyanate
(PharMingen, La Jolla, CA) according to manufacturer’s
directions. Processed cells were analyzed by flow cytometry on a Becton
Dickinson (San Jose, CA) Facscan.
Statistical Analysis
Comparison of data from gal3+/+ and gal3-/- mice were performed with the statistical software Statview. Data were subjected to the Mann-Whitney U test or analysis of variance with Bonferroni-Dunn post hoc analysis.
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Results |
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The genomic structure of galectin-3 contains six
exons39
(Figure 1A)
, with exons 2 and 3 coding for the
amino-terminal region and exons 4–6 coding for the carboxyl-terminal
carbohydrate-binding domain. Our strategy for inactivating galectin-3
in mice was to interrupt the region coding for the carbohydrate-binding
domain with a neomycin resistance gene. Specifically, a short intron
4-exon 5 segment (0.5 kb) was substituted with the
antibiotic-resistance gene (Neo). Figure 1B
depicts the structure of
the homologous recombinant galectin-3 gene and Figure 1C
predicts the
restriction fragment profiles of both wild type and homologous
recombinants using the specific probes shown in Figure 1B
. The genomic
Southern blot of two homologous recombinant
gal3+/- mouse embryonic stem cell clones is
shown in Figure 1D
, visualized with probe 1. The upper band in each
lane for clones 4A2 and 9A4 were detected with probe 4, but no bands
were observed in parent D3 (data not shown).
Figure 2A
shows the Southern blot
analysis of galectin-3 gene from gal3-/-,
gal3+/+, and gal3+/- mice.
The 2.9-kb intron 3-exon 5 fragment of the
galectin-3+/+ gene and the corresponding 4-kb
homologous recombinant of the galectin-3-/- are
evident. Hemizygous mice are characterized by the presence of both DNA
fragments. To demonstrate that the galectin-3 gene was indeed
inactivated in gal3-/- mice, several organ
extracts were prepared and adsorbed with lactosyl-Sepharose 4B, and the
adsorbed proteins were analyzed by immunoblotting. As shown in Figure 2B
, although gal3+/+ mice expressed large
amounts of galectin-3 in lung, spleen, and thymus tissues,
gal3-/- mice were deficient in this protein in
these various organs, as expected. Gal3-/- mice
are viable and fertile and do not exhibit any overt defects. Various
organs from gal3-/- mice were further examined
histologically and no apparent alterations were detected. Organs
examined included adrenal gland, brain, colon, duodenum, esophagus,
gall bladder, heart, hypophysis, kidney, knee joint, liver, lung, lymph
nodes, mesentery, ovary, pancreas, salivary glands, skeletal muscle,
skin, small intestine, stomach, spleen, testis, thymus, thyroid, and
urinary bladder. No significant differences were observed in body
weights and weights of major organs, and no differences were found in
blood cell counts and chemistry profiles between
gal3-/- and gal3+/+ mice.
Lymphocyte subpopulations of thymus, spleen, and lymph node were also
examined and total numbers of lymphocytes, ratios of
CD4+/CD8+ cells, and
numbers of CD3+ cells, were comparable between
gal3-/- and gal3+/+ mice.
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As an initial approach to assess the effect of galectin-3
deficiency on inflammatory responses, we examined the peritoneal
inflammation induced by thioglycollate broth. Untreated (Day 0)
gal3-/- mice consistently contained fewer
leukocytes in the peritoneal cavities, although the differences were
not statistically significant (P = 0.1879).
Although both types of mice mounted inflammatory responses to
thioglycollate broth treatment, gal3-/- mice
clearly exhibited reduced inflammation (Figure 3
, Table 1
). One day after thioglycollate broth
stimulation, the yields of inflammatory leukocytes in the peritoneal
cavities of gal3-/- mice were significantly
lower (P < 0.05) than that of
gal3+/+ mice (Figure 3)
. Similar trends were
observed 3 and 6 days after thioglycollate stimulation (Table 1)
.
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,
Table 2
). Although minor differences were
observed at day 0 (untreated mice), the most striking difference is the
substantially lower numbers of monocytes/macrophages and lymphocytes in
gal3-/- mice 1 day after thioglycollate broth
stimulation (Figure 3)
. The numbers of monocytes/macrophages were
comparable between the two groups of mice, however, on prolonged
inflammation for several days (Table 2)
. In contrast,
gal3-/- mice continued to exhibit significantly
lower numbers of lymphocytes on days 2 and 4 (Table 2)
. On the other
hand, the numbers of neutrophils were comparable, and there were
consistently more eosinophils in gal3-/- mice,
2 days after the stimulation. The difference between the two groups of
mice was also evident when the percentages of various leukocytes in the
peritoneal cavity were compared (Table 2)
. When compared with
gal3+/+ mice, gal3-/-
mice have lower percentages of monocytes/macrophages (day 1), lower
percentages of lymphocytes (days 2 and 4), and higher percentages of
eosinophils (days 1, 2, and 4).
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B Responses
The results reported above suggest that
gal3-/- mice develop a lower inflammatory
response to thioglycollate stimulation compared with
gal3+/+ mice. To substantiate this conclusion, we
examined the NF-B response in the peritoneal inflammatory cells in
these mice. NF-B is a transcription factor commonly activated in
various inflammatory conditions and plays an important role in the
transcription of genes for many inflammatory factors.48
Nuclear extracts were prepared from peritoneal leukocytes obtained from
untreated mice and mice treated with thioglycollate broth, and the B
binding activity was examined by EMSA. Resting peritoneal leukocytes
from untreated mice of both genotypes showed low levels of B binding
activity. However, on stimulation with thioglycollate broth, leukocytes
from gal3+/+ mice responded with robust B
binding activities. In contrast, leukocytes from
gal3-/- mice responded weakly (Figure 4A)
.
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B response in cells from
gal3-/- mice are consistent with decreased
levels of activation. However, another possibility is an intrinsic
deficit in the NF-B response pathway as a result of the galectin-3
deficiency. To differentiate these two possibilities, we obtained
resting as well as thioglycollate-elicited peritoneal leukocytes from
both genotypes, exposed them to tumor necrosis factor-
(TNF-),
and measured the NF-B response. As shown in Figure 4B
, resting cells
from both genotypes exhibited nearly undetectable levels of B
binding activity, but showed comparable levels of activity on
stimulation by TNF. Similarly, while thioglycollate-elicited
leukocytes from gal3-/- mice exhibited
significantly reduced levels of B binding activity compared with
gal3+/+ mice, cells from both genotypes showed
comparable levels of activity after stimulation by TNF. Therefore,
the gal3-/- cells do not appear to have an
intrinsic defect in NF-B response and the lower response in the
peritoneal cells of gal3-/- mice following
thioglycollate treatment probably reflects the lower degree of
peritoneal inflammation in these mice. Peritoneal Macrophages from gal3-/- Mice Show Decreased Areas of Adherence in Culture
When resident or thioglycollate-elicited peritoneal macrophages
from gal3-/- mice and
gal3+/+ mice were cultured under standard
conditions, the adherent cells from both sources exhibited
spread-out morphology characteristic of macrophages. However, we
consistently observed that cultured resident macrophages from
gal3-/- mice exhibited a lower degree of
spreading. Indeed, when the cell surface areas were measured,
statistically significant differences were noted (178 ± 2
vs. 151 ± 2 relative units for
gal3+/+ and gal3-/- mice,
respectively, from a total of 5 experiments, 13 mice, and over 3300
cells from each genotype measured, P < 0.0001). When
thioglycollate-elicited peritoneal cells were cultured for 2 hours and
initially nonadherent cells (containing monocytes, lymphocytes,
eosinophils, and neutrophils) were further cultured, an additional
macrophage population could be obtained. When these cell populations
were compared, a dramatic difference in the degrees of spreading was
observed (Figure 5A)
. The average cell
area of adherent macrophages from gal3-/- mice
was less than 40% of that of cells from gal3+/+
mice (Figure 5B)
. The experiments were performed four times with cells
from a total of eight mice for each genotype. Cells from
gal3-/- mice often exhibited spindle-shaped
morphology in 22 out of 24 culture wells, while cells from
gal3+/+ mice showed more uniform spread-out
morphology in all 24 culture wells.
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Macrophages from gal3-/- Mice Are More Sensitive to Apoptotic Stimuli
Previously, we have shown that Jurkat cells transfected with
galectin-3 cDNA and expressing this lectin are more resistant to
apoptosis induced by anti-Fas antibodies and staurosporine compared
with control transfectant not expressing the lectin,24
and
concluded that galectin-3 functions as an anti-apoptotic protein.
Therefore, it is possible that the lower levels of peritoneal
inflammatory cells in gal3-/- mice are at least
partly attributable to the increased cell death in these mice due to
the lack of this lectin. To test this possibility, we compared the rate
of apoptosis of peritoneal macrophages from
gal3+/+ and gal3-/- mice
after treatment with IFN- and LPS, a procedure known to induce
apoptosis in these cells.49
We focused on macrophages
because these cells are known to express galectin-3.50
The
mice were injected intraperitoneally with thioglycollate, and harvested
inflammatory peritoneal macrophages were treated with 10 µg/ml LPS
and 10 U/ml IFN- for various periods. As shown in Figure 6A
, viable cells decreased with time in
culture. Gal3-/- cells appeared to be more
sensitive to this treatment and resulted in significantly lower numbers
of surviving cells. With the alternative method of activation, where
macrophages were pretreated with IFN- for 6 hours before LPS,
significantly decreased numbers of cells were observed for doses of
IFN- from 0.3 to 10 U/ml in a dose-dependent manner (data not
shown). Because LPS/IFN--induced apoptosis occurs through a nitric
oxide-dependent pathway,51-53
levels of nitrite (a stable
by-product of nitric oxide) in culture supernatants were measured. No
significant differences were observed between
gal3+/+ and gal3-/-
macrophage cultures (data not shown), suggesting that differential rate
of cell death was not due to differences in the capacity to produce
nitric oxide after LPS and IFN- activation.
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and LPS as above to
induce apoptosis. As shown in Figure 6B
, macrophages from
gal3-/- mice demonstrated significantly higher
levels of apoptosis, as confirmed by higher annexin-V binding. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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B response. The results suggest
that endogenous galectin-3 plays a role in positively regulating
peritoneal inflammatory processes. Results from a number of previous in vitro studies have suggested that galectin-3 may be an amplifier of inflammatory responses. First, galectin-3 is present in extracellular fluid and is capable of activating various cells.8,54 Thus, it may be envisaged that in inflammatory responses in the peritoneal cavity, galectin-3 released from some of the activated cells could activate additional cells. Second, this lectin can mediate cell-cell and cell-extracellular matrix protein interactions,19,21,55 as well as homotypic cell-cell interactions,20 making it suited for promoting inflammatory responses. Third, galectin-3 can inhibit programmed cell death, as demonstrated by using a human T cell line transfected with galectin-3 cDNA.24 Therefore, galectin-3 expression may lead to longer survival of inflammatory cells and thus to prolonged inflammation. The results reported here, indeed, support the previous notion that galectin-3 has a proinflammatory function. Furthermore, at least one of the above mechanisms may be contributory. Specifically, galectin-3 deficiency appears to result in the peritoneal macrophages becoming more sensitive to apoptotic stimuli, resulting in mice exhibiting decreased levels of inflammation.
The finding that galectin-3 deficiency results in increased tendency to apoptosis in macrophages in turn supports the function of galectin-3 in inhibiting apoptosis. Previously, we noted sequence similarity between galectin-3 and a well-characterized anti-apoptotic protein, Bcl-2, demonstrated binding of Bcl-2 by galectin-3, and proposed that galectin-3 inhibits apoptosis, possibly through a mechanism involving interaction with Bcl-2. Although we do not have additional information on the mechanism underlying the anti-apoptotic activity of galectin-3, we believe this molecule exerts this effect through intracellular action. One piece of supporting evidence for this notion is that recombinant galectin-3 added exogenously to cultured peritoneal macrophages did not affect the cell survival (data not shown). This finding is consistent with a previous report where galectin-3 does not induce apoptosis of thymocytes when added exogenously.56 The mechanism of galectin-3 for regulating apoptosis is thus different from that of galectin-1, which has been shown to induce apoptosis of thymocytes through binding to cell surface glycoconjugates.57,58
We cannot exclude the possibility that galectin-3 also affects the overall peritoneal inflammatory responses through extracellular functions, especially because abundant amounts of galectin-3 exist in the peritoneal exudate, and this protein is known to bind to cell surface glycoconjugates through lectin-carbohydrate interactions.50 We have attempted to use anti-galectin-3 antibodies to further clarify the role of extracellular galectin-3 in the inflammatory responses. We have previously generated a number of monoclonal antibodies against galectin-3. Only one of them (B2C10) has blocking activity, whereas others (eg, A3A12) potentiate galectin-3 lectin activities. We found that, when injected into peritoneal cavity of wild-type C57BL/6 mice, A3A12 caused an increase and B2C10 caused a decrease in the numbers of inflammatory cells in the peritoneal cavity elicited by thioglycollate, compared with an isotype-matched control monoclonal antibody. Although the potentiating and suppressive effects of the two antibodies compared with the control antibody were not statistically significant, the differences between the two were (data not shown). Therefore, these preliminary data support extracellular functions of galectin-3. Further clarification would require more potent blocking antibodies or other specific inhibitors against galectin-3. Additional experiments are also required to determine the relative contribution of the intracellular functions of this lectin to its regulation of inflammatory responses. Thus, the possible mechanisms of action we propose include both intracellular and extracellular functions of galectin-3. In fact, our present view is that this lectin as well as other members of this lectin family function both inside and outside the cell. This is based on the existence of the lectin as well as galectin-3-interacting proteins in both compartments, and demonstrated extracellular (eg, activation of cells and promotion of cell adhesion) and intracellular functions (eg, engagement in pre-mRNA splicing and regulation of apoptosis) in vitro.
Because the extent of cell spreading is reflective of cell activation, the fact that macrophages from gal3+/+ mice exhibit more extended morphologies is also consistent with our proposition that cells from these mice are more activated. However, other explanations need to be considered. The most obvious is that galectin-3 released by monocytes/macrophages, a cell type known to contain high levels of the lectin,12,59 directly mediates cell adhesion and spreading. However, this may not be in operation because the spreading of macrophages from gal3+/+ mice was unaffected when the cells were cultured in the presence of lactose (data not shown), which should inhibit extracellular galectin-3 activities. It has recently been reported that galectin-3 binds to and colocalizes with cytokeratin60 in a fashion that is dependent on carbohydrate residues on cytokeratin. Therefore, an attractive alternative is that galectin-3-cytokeratin interactions modulate the cell shape. It is to be noted that the effect of galectin-3 deficiency on cell shape is much more pronounced in initially nonadherent cells, as compared with the initially adherent cells; the former are likely to include more immature monocytes and the latter represent mature macrophages. It is possible that during maturation of macrophages in vivo to the inflammatory state, any defects in in vitro adherence and spreading caused by galectin-3 deficiency may be partially overcome. On the other hand, conditions imposed by culturing initially nonadherent monocytes may accentuate defects in adherence and spreading properties of these cells resulting from galectin-3 deficiency. These results also suggest the possibility that cell types such as lymphocytes, neutrophils, and eosinophils included in the initially nonadherent cell population may influence the spreading of monocytes/macrophages by providing some specific signals, and these companion cells from gal3+/+ mice may be more activated than those from gal3-/- mice.
While this work was in progress, Colnot et al reported findings made with an independent line of galectin-3-deficient mice.61 The main defect noted is that gal3-/- mice have significantly reduced numbers of neutrophils in the peritoneal cavity 4 days after thioglycollate treatment, which was not seen in our experiments. This could be due to variations in the constituents of the thioglycollate broth used as well as the amounts injected, which might have resulted in both quantitative and qualitative differences in the response. On the other hand, these investigators also observed lower numbers of macrophages in gal3-/- mice on day 1 after thioglycollate treatment, as compared with the wild-type mice (19.0 ± 2.53 vs. 31.1 ± 6.24). Although the difference is not statistically significant, it is conceivable that a statistically significant difference would be observed with a larger number of mice. Considering both studies together, the evidence is convincing that galectin-3-deficient mice mount a lower initial monocyte/macrophage response than wild-type mice.
The finding that galectin-3-deficient mice have attenuated peritoneal inflammatory responses lends strong support for the role of galectin-3 in augmentation of inflammation. The results provide new insights into mechanisms by which galectin-3 exerts its proinflammatory function, especially when considered together with information from previous in vitro studies. In particular, this lectin may contribute to inflammation by regulating apoptosis of inflammatory cells under inflammatory conditions. Additional studies with this mouse model should allow further elucidation of the function of galectin-3 in various inflammatory situations, as well as development of inhibitors of galectin-3 as therapeutic agents for suppressing inflammatory responses. In addition, the gal3-/- mice should be valuable for delineation of the role of this lectin in other pathological processes, especially the neoplasm.
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Acknowledgements |
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Footnotes |
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Supported by National Institutes of Health grants AI-20958 and AI-39620.
Accepted for publication November 2, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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BP, a ß-galactoside-binding animal lectin, recognizes IgE receptor (FcRI), and activates mast cells. Biochemistry 1993, 32:7644-7649[Medline]
BP, an IgE-binding endogenous lectin. Cell Immunol 1994, 156:1-12[Medline]
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GalNAc containing glycans on cytokeratins are recognized in vitro by galectins with type II carbohydrate recognition domains. J Cell Sci 1997, 110:1585-1596[Abstract]
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 P. Mina-Osorio, B. Winnicka, C. O'Conor, C. L. Grant, L. K. Vogel, D. Rodriguez-Pinto, K. V. Holmes, E. Ortega, and L. H. Shapiro CD13 is a novel mediator of monocytic/endothelial cell adhesion J. Leukoc. Biol., August 1, 2008; 84(2): 448 - 459. [Abstract] [Full Text] [PDF]
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 S. Bi, L. A. Earl, L. Jacobs, and L. G. Baum Structural Features of Galectin-9 and Galectin-1 That Determine Distinct T Cell Death Pathways J. Biol. Chem., May 2, 2008; 283(18): 12248 - 12258. [Abstract] [Full Text] [PDF]
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J. M. Torkko, A. Manninen, S. Schuck, and K. Simons Depletion of apical transport proteins perturbs epithelial cyst formation and ciliogenesis J. Cell Sci., April 15, 2008; 121(8): 1193 - 1203. [Abstract] [Full Text] [PDF]
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S. R. Stowell, C. M. Arthur, P. Mehta, K. A. Slanina, O. Blixt, H. Leffler, D. F. Smith, and R. D. Cummings Galectin-1, -2, and -3 Exhibit Differential Recognition of Sialylated Glycans and Blood Group Antigens J. Biol. Chem., April 11, 2008; 283(15): 10109 - 10123. [Abstract] [Full Text] [PDF]
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M. Papaspyridonos, E. McNeill, J. P. de Bono, A. Smith, K. G. Burnand, K. M. Channon, and D. R. Greaves Galectin-3 Is an Amplifier of Inflammation in Atherosclerotic Plaque Progression Through Macrophage Activation And Monocyte Chemoattraction Arterioscler Thromb Vasc Biol, March 1, 2008; 28(3): 433 - 440. [Abstract] [Full Text] [PDF]
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J. Nieminen, C. St-Pierre, P. Bhaumik, F. Poirier, and S. Sato Role of Galectin-3 in Leukocyte Recruitment in a Murine Model of Lung Infection by Streptococcus pneumoniae J. Immunol., February 15, 2008; 180(4): 2466 - 2473. [Abstract] [Full Text] [PDF]
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S. L. Farnworth, N. C. Henderson, A. C. MacKinnon, K. M. Atkinson, T. Wilkinson, K. Dhaliwal, K. Hayashi, A. J. Simpson, A. G. Rossi, C. Haslett, et al. Galectin-3 Reduces the Severity of Pneumococcal Pneumonia by Augmenting Neutrophil Function Am. J. Pathol., February 1, 2008; 172(2): 395 - 405. [Abstract] [Full Text] [PDF]
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 C Boileau, F Poirier, J-P Pelletier, M Guevremont, N Duval, J Martel-Pelletier, and P Reboul Intracellular localisation of galectin-3 has a protective role in chondrocyte survival Ann Rheum Dis, February 1, 2008; 67(2): 175 - 181. [Abstract] [Full Text] [PDF]
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M. Nachtigal, A. Ghaffar, and E. P. Mayer Galectin-3 Gene Inactivation Reduces Atherosclerotic Lesions and Adventitial Inflammation in ApoE-Deficient Mice Am. J. Pathol., January 1, 2008; 172(1): 247 - 255. [Abstract] [Full Text] [PDF]
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 L. Breuilh, F. Vanhoutte, J. Fontaine, C. M. W. van Stijn, I. Tillie-Leblond, M. Capron, C. Faveeuw, T. Jouault, I. van Die, P. Gosset, et al. Galectin-3 Modulates Immune and Inflammatory Responses during Helminthic Infection: Impact of Galectin-3 Deficiency on the Functions of Dendritic Cells Infect. Immun., November 1, 2007; 75(11): 5148 - 5157. [Abstract] [Full Text] [PDF]
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 F. H.M. de Melo, D. Butera, R. S. Medeiros, L. N. d. S. Andrade, S. Nonogaki, F. A. Soares, R. A. Alvarez, A. M. Moura da Silva, and R. Chammas Biological Applications of a Chimeric Probe for the Assessment of Galectin-3 Ligands J. Histochem. Cytochem., October 1, 2007; 55(10): 1015 - 1026. [Abstract] [Full Text] [PDF]
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G. Konopka, J. Tekiela, M. Iverson, C. Wells, and S. A. Duncan Junctional Adhesion Molecule-A Is Critical for the Formation of Pseudocanaliculi and Modulates E-cadherin Expression in Hepatic Cells J. Biol. Chem., September 21, 2007; 282(38): 28137 - 28148. [Abstract] [Full Text] [PDF]
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F. L. Oliveira, P. Frazao, R. Chammas, D. K. Hsu, F. T. Liu, R. Borojevic, C. M. Takiya, and M. C. El-Cheikh Kinetics of mobilization and differentiation of lymphohematopoietic cells during experimental murine schistosomiasis in galectin-3 / mice J. Leukoc. Biol., August 1, 2007; 82(2): 300 - 310. [Abstract] [Full Text] [PDF]
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E. Silva-Monteiro, L. Reis Lorenzato, O. Kenji Nihei, M. Junqueira, G. A. Rabinovich, D. K. Hsu, F.-T. Liu, W. Savino, R. Chammas, and D. M. S. Villa-Verde Altered Expression of Galectin-3 Induces Cortical Thymocyte Depletion and Premature Exit of Immature Thymocytes during Trypanosoma cruzi Infection Am. J. Pathol., February 1, 2007; 170(2): 546 - 556. [Abstract] [Full Text] [PDF]
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 E Lippert, W Falk, F Bataille, T Kaehne, M Naumann, M Goeke, H Herfarth, J Schoelmerich, and G Rogler Soluble galectin-3 is a strong, colonic epithelial-cell-derived, lamina propria fibroblast-stimulating factor Gut, January 1, 2007; 56(1): 43 - 51. [Abstract] [Full Text] [PDF]
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P. Barrionuevo, M. Beigier-Bompadre, J. M. Ilarregui, M. A. Toscano, G. A. Bianco, M. A. Isturiz, and G. A. Rabinovich A Novel Function for Galectin-1 at the Crossroad of Innate and Adaptive Immunity: Galectin-1 Regulates Monocyte/Macrophage Physiology through a Nonapoptotic ERK-Dependent Pathway J. Immunol., January 1, 2007; 178(1): 436 - 445. [Abstract] [Full Text] [PDF]
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M. G. Chiu, T. M. Johnson, A. S. Woolf, E. M. Dahm-Vicker, D. A. Long, L. Guay-Woodford, K. A. Hillman, S. Bawumia, K. Venner, R. C. Hughes, et al. Galectin-3 Associates with the Primary Cilium and Modulates Cyst Growth in Congenital Polycystic Kidney Disease Am. J. Pathol., December 1, 2006; 169(6): 1925 - 1938. [Abstract] [Full Text] [PDF]
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 V. G. Prieto, A. A. Mourad-Zeidan, V. Melnikova, M. M. Johnson, A. Lopez, A. H. Diwan, A. J.F. Lazar, S. S. Shen, P. S. Zhang, J. A. Reed, et al. Galectin-3 Expression Is Associated with Tumor Progression and Pattern of Sun Exposure in Melanoma. Clin. Cancer Res., November 15, 2006; 12(22): 6709 - 6715. [Abstract] [Full Text] [PDF]
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H.-Y. Chen, B. B. Sharma, L. Yu, R. Zuberi, I-C. Weng, Y. Kawakami, T. Kawakami, D. K. Hsu, and F.-T. Liu Role of Galectin-3 in Mast Cell Functions: Galectin-3-Deficient Mast Cells Exhibit Impaired Mediator Release and Defective JNK Expression J. Immunol., October 15, 2006; 177(8): 4991 - 4997. [Abstract] [Full Text] [PDF]
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 B. Cecchinelli, L. Lavra, C. Rinaldo, S. Iacovelli, A. Gurtner, A. Gasbarri, A. Ulivieri, F. Del Prete, M. Trovato, G. Piaggio, et al. Repression of the Antiapoptotic Molecule Galectin-3 by Homeodomain-Interacting Protein Kinase 2-Activated p53 Is Required for p53-Induced Apoptosis Mol. Cell. Biol., June 15, 2006; 26(12): 4746 - 4757. [Abstract] [Full Text] [PDF]
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E. S. Bernardes, N. M. Silva, L. P. Ruas, J. R. Mineo, A. M. Loyola, D. K. Hsu, F.-T. Liu, R. Chammas, and M. C. Roque-Barreira Toxoplasma gondii Infection Reveals a Novel Regulatory Role for Galectin-3 in the Interface of Innate and Adaptive Immunity Am. J. Pathol., June 1, 2006; 168(6): 1910 - 1920. [Abstract] [Full Text] [PDF]
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 N. C. Henderson, A. C. Mackinnon, S. L. Farnworth, F. Poirier, F. P. Russo, J. P. Iredale, C. Haslett, K. J. Simpson, and T. Sethi Galectin-3 regulates myofibroblast activation and hepatic fibrosis PNAS, March 28, 2006; 103(13): 5060 - 5065. [Abstract] [Full Text] [PDF]
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J. Nieminen, C. St-Pierre, and S. Sato Galectin-3 interacts with naive and primed neutrophils, inducing innate immune responses J. Leukoc. Biol., November 1, 2005; 78(5): 1127 - 1135. [Abstract] [Full Text] [PDF]
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J M Ilarregui, G A Bianco, M A Toscano, and G A Rabinovich The coming of age of galectins as immunomodulatory agents: impact of these carbohydrate binding proteins in T cell physiology and chronic inflammatory disorders Ann Rheum Dis, November 1, 2005; 64(suppl_4): iv96 - iv103. [Abstract] [Full Text] [PDF]
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 D. Chauhan, G. Li, K. Podar, T. Hideshima, P. Neri, D. He, N. Mitsiades, P. Richardson, Y. Chang, J. Schindler, et al. A Novel Carbohydrate-Based Therapeutic GCS-100 Overcomes Bortezomib Resistance and Enhances Dexamethasone-Induced Apoptosis in Multiple Myeloma Cells Cancer Res., September 15, 2005; 65(18): 8350 - 8358. [Abstract] [Full Text] [PDF]
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N. Oka, S. Nakahara, Y. Takenaka, T. Fukumori, V. Hogan, H.-o. Kanayama, T. Yanagawa, and A. Raz Galectin-3 Inhibits Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand-Induced Apoptosis by Activating Akt in Human Bladder Carcinoma Cells Cancer Res., September 1, 2005; 65(17): 7546 - 7553. [Abstract] [Full Text] [PDF]
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 C. Iacobini, G. Oddi, S. Menini, L. Amadio, C. Ricci, C. Di Pippo, M. Sorcini, F. Pricci, F. Pugliese, and G. Pugliese Development of age-dependent glomerular lesions in galectin-3/AGE-receptor-3 knockout mice Am J Physiol Renal Physiol, September 1, 2005; 289(3): F611 - F621. [Abstract] [Full Text] [PDF]
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H. Shoji, K. Ikenaka, S.-i. Nakakita, K. Hayama, J. Hirabayashi, Y. Arata, K.-i. Kasai, N. Nishi, and T. Nakamura Xenopus galectin-VIIa binds N-glycans of members of the cortical granule lectin family (xCGL and xCGL2) Glycobiology, July 1, 2005; 15(7): 709 - 720. [Abstract] [Full Text] [PDF]
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 K. Sato, Y. Imai, N. Higashi, Y. Kumamoto, T. M. Onami, S. M. Hedrick, and T. Irimura Lack of antigen-specific tissue remodeling in mice deficient in the macrophage galactose-type calcium-type lectin 1/CD301a Blood, July 1, 2005; 106(1): 207 - 215. [Abstract] [Full Text] [PDF]
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 N. Ortega, D. J. Behonick, C. Colnot, D. N.W. Cooper, and Z. Werb Galectin-3 Is a Downstream Regulator of Matrix Metalloproteinase-9 Function during Endochondral Bone Formation Mol. Biol. Cell, June 1, 2005; 16(6): 3028 - 3039. [Abstract] [Full Text] [PDF]
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G. C. Fernandez, J. M. Ilarregui, C. J. Rubel, M. A. Toscano, S. A. Gomez, M. Beigier Bompadre, M. A. Isturiz, G. A. Rabinovich, and M. S. Palermo Galectin-3 and soluble fibrinogen act in concert to modulate neutrophil activation and survival: involvement of alternative MAPK pathways Glycobiology, May 1, 2005; 15(5): 519 - 527. [Abstract] [Full Text] [PDF]
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 A. W. Stitt, C. McGoldrick, A. Rice-McCaldin, D. R. McCance, J. V. Glenn, D. K. Hsu, F.-T. Liu, S. R. Thorpe, and T. A. Gardiner Impaired Retinal Angiogenesis in Diabetes: Role of Advanced Glycation End Products and Galectin-3 Diabetes, March 1, 2005; 54(3): 785 - 794. [Abstract] [Full Text] [PDF]
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R. I. Zuberi, D. K. Hsu, O. Kalayci, H.-Y. Chen, H. K. Sheldon, L. Yu, J. R. Apgar, T. Kawakami, C. M. Lilly, and F.-T. Liu Critical Role for Galectin-3 in Airway Inflammation and Bronchial Hyperresponsiveness in a Murine Model of Asthma Am. J. Pathol., December 1, 2004; 165(6): 2045 - 2053. [Abstract] [Full Text] [PDF]
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Y. Takenaka, T. Fukumori, T. Yoshii, N. Oka, H. Inohara, H.-R. C. Kim, R. S. Bresalier, and A. Raz Nuclear Export of Phosphorylated Galectin-3 Regulates Its Antiapoptotic Activity in Response to Chemotherapeutic Drugs Mol. Cell. Biol., May 15, 2004; 24(10): 4395 - 4406. [Abstract] [Full Text] [PDF]
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M. Dias-Baruffi, H. Zhu, M. Cho, S. Karmakar, R. P. McEver, and R. D. Cummings Dimeric Galectin-1 Induces Surface Exposure of Phosphatidylserine and Phagocytic Recognition of Leukocytes without Inducing Apoptosis J. Biol. Chem., October 17, 2003; 278(42): 41282 - 41293. [Abstract] [Full Text] [PDF]
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R. G. Jenner, K. Maillard, N. Cattini, R. A. Weiss, C. Boshoff, R. Wooster, and P. Kellam Kaposi's sarcoma-associated herpesvirus-infected primary effusion lymphoma has a plasma cell gene expression profile PNAS, September 2, 2003; 100(18): 10399 - 10404. [Abstract] [Full Text] [PDF]
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H. Shoji, N. Nishi, M. Hirashima, and T. Nakamura Characterization of the Xenopus Galectin Family. THREE STRUCTURALLY DIFFERENT TYPES AS IN MAMMALS AND REGULATED EXPRESSION DURING EMBRYOGENESIS J. Biol. Chem., March 28, 2003; 278(14): 12285 - 12293. [Abstract] [Full Text] [PDF]
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S. G. Correa, C. E. Sotomayor, M. P. Aoki, C. A. Maldonado, and G. A. Rabinovich Opposite effects of galectin-1 on alternative metabolic pathways of L-arginine in resident, inflammatory, and activated macrophages Glycobiology, February 1, 2003; 13(2): 119 - 128. [Abstract] [Full Text] [PDF]
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Z. Cao, N. Said, S. Amin, H. K. Wu, A. Bruce, M. Garate, D. K. Hsu, I. Kuwabara, F.-T. Liu, and N. Panjwani Galectins-3 and -7, but not Galectin-1, Play a Role in Re-epithelialization of Wounds J. Biol. Chem., October 25, 2002; 277(44): 42299 - 42305. [Abstract] [Full Text] [PDF]
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J. D. Hernandez and L. G. Baum Ah, sweet mystery of death! Galectins and control of cell fate Glycobiology, October 1, 2002; 12(10): 127R - 136R. [Abstract] [Full Text] [PDF]
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 V. del Pozo, M. Rojo, M. L. Rubio, I. Cortegano, B. Cardaba, S. Gallardo, M. Ortega, E. Civantos, E. Lopez, C. Martin-Mosquero, et al. Gene Therapy with Galectin-3 Inhibits Bronchial Obstruction and Inflammation in Antigen-challenged Rats through Interleukin-5 Gene Downregulation Am. J. Respir. Crit. Care Med., September 1, 2002; 166(5): 732 - 737. [Abstract] [Full Text] [PDF]
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F. Yu, R. L. Finley Jr., A. Raz, and H.-R. C. Kim Galectin-3 Translocates to the Perinuclear Membranes and Inhibits Cytochrome c Release from the Mitochondria. A ROLE FOR SYNEXIN IN GALECTIN-3 TRANSLOCATION J. Biol. Chem., May 3, 2002; 277(18): 15819 - 15827. [Abstract] [Full Text] [PDF]
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G. A. Rabinovich, N. Rubinstein, and L. Fainboim Unlocking the secrets of galectins: a challenge at the frontier of glyco-immunology J. Leukoc. Biol., May 1, 2002; 71(5): 741 - 752. [Abstract] [Full Text] [PDF]
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S. Sato, N. Ouellet, I. Pelletier, M. Simard, A. Rancourt, and M. G. Bergeron Role of Galectin-3 as an Adhesion Molecule for Neutrophil Extravasation During Streptococcal Pneumonia J. Immunol., February 15, 2002; 168(4): 1813 - 1822. [Abstract] [Full Text] [PDF]
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A. Orlofsky, L. M. Weiss, N. Kawachi, and M. B. Prystowsky Deficiency in the Anti-Apoptotic Protein A1-a Results in a Diminished Acute Inflammatory Response J. Immunol., February 15, 2002; 168(4): 1840 - 1846. [Abstract] [Full Text] [PDF]
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J. Mengwasser, F.-T. Liu, and J. P. Sleeman Galectin-3 is strongly up-regulated in nonapoptosing mammary epithelial cells during rat mammary gland involution Glycobiology, February 1, 2002; 12(2): 129 - 134. [Abstract] [Full Text] [PDF]
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 G. PUGLIESE, F. PRICCI, C. IACOBINI, G. LETO, L. AMADIO, P. BARSOTTI, L. FRIGERI, D. K. HSU, H. VLASSARA, F.-T. LIU, et al. Accelerated diabetic glomerulopathy in galectin-3/AGE receptor 3 knockout mice FASEB J, November 1, 2001; 15(13): 2471 - 2479. [Abstract] [Full Text] [PDF]
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 E. Hrdlickova-Cela, J. Plzak, K. Smetana Jr, Z. Melkova, H. Kaltner, M. Filipec, F.-T. Liu, and H.-J. Gabius Detection of galectin-3 in tear fluid at disease states and immunohistochemical and lectin histochemical analysis in human corneal and conjunctival epithelium Br J Ophthalmol, November 1, 2001; 85(11): 1336 - 1340. [Abstract] [Full Text] [PDF]
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B.-K. Moon, Y. J. Lee, P. Battle, J. M. Jessup, A. Raz, and H.-R. C. Kim Galectin-3 Protects Human Breast Carcinoma Cells against Nitric Oxide-Induced Apoptosis : Implication of Galectin-3 Function during Metastasis Am. J. Pathol., September 1, 2001; 159(3): 1055 - 1060. [Abstract] [Full Text] [PDF]
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H. Sano, D. K. Hsu, L. Yu, J. R. Apgar, I. Kuwabara, T. Yamanaka, M. Hirashima, and F.-T. Liu Human Galectin-3 Is a Novel Chemoattractant for Monocytes and Macrophages J. Immunol., August 15, 2000; 165(4): 2156 - 2164. [Abstract] [Full Text] [PDF]
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R.-Y. Yang, D. K. Hsu, L. Yu, J. Ni, and F.-T. Liu Cell Cycle Regulation by Galectin-12, a New Member of the Galectin Superfamily J. Biol. Chem., June 1, 2001; 276(23): 20252 - 20260. [Abstract] [Full Text] [PDF]
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